Tryptophan depletion generates hyper-reactive portal neutrophils in alcoholic liver disease

BACKGROUND: Neutrophils guarantee a prompt and robust host response to pathogens. Yet, overshooting neutrophil activation leads to tremendous collateral damage in tissues. In advanced chronic liver disease (ACLD), neutrophils are exposed to the highly immunogenic milieu of the portal circulation prior to entering the liver sinusoids. In alcohol-related liver disease (ALD), neutrophils occupy a central role and therefore mechanisms regulating neutrophil activity pose a possible therapeutic target. OBJECTIVE: Evaluate the impact of the portal milieu on neutrophils in ACLD with portal hypertension. DESIGN: We conducted a prospective study of patients undergoing transjugular intrahepatic portosystemic shunt placement. Paired blood samples were obtained from the portal vein (PV) and superior vena cava (SVC); the neutrophil phenotype was assessed by spectral flow cytometry; plasma was analysed by cytokine quantification, reporter assays and metabolomics. Effects of tryptophan supplementation on neutrophil function and phenotype were tested in isolated neutrophils. RESULTS: neutrophils in the portal circulation. PV plasma induced this phenotype in SVC neutrophils. Analysis of portal plasma revealed no differences in cytokines or toll-like receptor (TLR)/nucleotide-binding oligomerisation domain-containing protein (NOD) ligands but decreased local tryptophan concentrations in patients with ALD. In vitro supplementation of tryptophan ameliorated activation of isolated neutrophils. CONCLUSION: Our findings identify portal tryptophan as a local regulator of neutrophil activation in ACLD. The link between low tryptophan levels and heightened neutrophil reactivity, especially in ALD, underscores the role of the gut-liver metabolic crosstalk in immune modulation and highlights a potential therapeutic target for mitigating neutrophil-driven liver injury.